Several compositions of micro- and nano-particle suspensions of water-insoluble or poorly water-soluble biologically active substances such as pharmaceutical agents, and methods to prepare such suspensions have been described in patent literature. These compositions use surfactant molecules as surface modifiers that associate on the surface of the micro- or nano-particles and inhibit the growth of their size. Such surface stabilized microparticles may be administered to elicit their pharmaceutical advantage by injectable or oral or other routes of administration.
Drug delivery systems utilizing microparticulate suspensions have been described in literature (D. H. Haynes, “Phospholipid-coated Microcrystals: Injectable Formulations of Water-Insoluble Drugs.” U.S. Pat. Nos. 5,091,187 and 5,091,188). These suspensions are believed to be the first applications of the surface modified microparticulate aqueous suspension containing particles made up of a core of pure drug substances and stabilized with natural or synthetic bipolar lipids including phospholipids and cholesterol. Subsequently, similar delivery systems exploiting these principles have been described (G. G. Liversidge et al., “Surface Modified Drug Nanoparticles.” U.S. Pat. No. 5,145,684 K. J. Illig and P. Sarpotdar, “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability.” U.S. Pat. No. 5,340,564 H. William Bosch et al., “Process for Preparing Therapeutic Compositions Containing Nanoparticles.” U.S. Pat. No. 5,510,118) emphasizing the usefulness of the drug delivery approach utilizing particulate aqueous suspensions.
Sterilization of the submicron- to micron-sized particle suspension of the pharmaceutical agent is necessary for their parenteral administration. The preferred method of sterilization of pharmaceutical parenteral agents is terminal sterilization by autoclaving. It has been found that many surface modified submicron- to micron-sized particle suspensions undergo particle size growth during autoclaving. This is attributed to the release of the surfactant molecules from the small particle surface and its subsequent coagulation at autoclaving temperatures. The small particles that are devoid of the surfactants become unstabilized and undergo particle size growth by various mechanisms. The temperature at which such coagulation of surfactant molecules occur is known as the cloud point of that surfactant. It is believed that addition of cloud point modifiers, which are merely other surfactants, raises the cloud point of the primary surfactant and thereby maintaining the surface modifier coating on the nanoparticles during autoclaving. The cloud point modifier molecules described in majority of the published literature (U.S. Pat. No. 5,298,262 U.S. Pat. No. 5,336,507, and U.S. Pat. No. 5,340,564) are ionic surfactants, including charged phospholipids.
Successful terminal steam sterilization of phospholipid-stabilized emulsions and phospholipid-liposomes have been reported in literature [1-4]. However, examples of successful terminal steam sterilization of micron or submicron size particle suspensions of water insoluble or poorly soluble drugs, that contain only phospholipids as the surface modifier, have not been reported prior to the findings reported in the present invention.